Schistosoma mansoni is a parasitic helminth of significant public health concern. Clinical disease is due to the granulomatous response to eggs that become trapped in the liver. In most people and all laboratory wild type mice, S. mansoni leads to the development of a strong Th2 response concurrent with the onset of parasite egg production. Although the granuloma induced by the Th2 response results in liver damage, it is critical for host protection. This is demonstrated in IL-4-/- mice during S. mansoni infection. These animals are unable to mount a Th2 response and suffer from debilitating cachexia and enhanced mortality subsequent to the onset of egg production. One of the aims of this proposal is to address the role of inflammatory mediators in the development of severe cachexia and mortality in IL-4-/- mice. During severe disease in schistosome-infected IL- 4-/- mice, splenocytes produce increased inflammatory mediators including NO and TNF-alpha, in vitro. TNF-alpha contributes to severe disease as treatment with anti- TNF-alpha antibody prolongs time to death in infected IL-4-/- mice. One hypothesis is that egg excretion results in increased endotoxin translocation across the gut wall and in mice lacking the ability to mount a Th2 responses, severe inflammation ensues. This hypothesis will be tested by generating IL-4-/- mouse strains that are hypo-responsive to LPS including IL-4/TNF-receptor-1, IL-4/CD14 double knockout strains and IL-4-/- mouse on an endotoxin resistant background (C3H Hej). The course of disease will be followed and in vitro responses seen in these strains; I anticipate that if endotoxin induces the severe disease in infected IL-4-/mice, cachexia and mortality will be minimized in endotoxin hypo-responsive animals. The second aim of this proposal focuses on determining the importance and cause of a defect in splenocyte proliferation that I have observed in infected IL-4-/- mice. Mediators such as TGF-beta and NO are elevated in IL-4-/- mice during infection and are potent inhibitors of T-cell proliferation. The role of these mediators in inhibiting the signal transduction cascade which leads to T-cell proliferation will be evaluated. The level at which proliferation is inhibited will be determined through analysis of activation of signaling proteins important in proliferative response and the levels of expression of cdks and cdk inhibitors.